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Derek Lowe's commentary on drug discovery and the pharma industry. An editorially independent blog from the publishers of Science Translational Medicine. All content is Derek’s own, and he does not in any way speak for his employer.

Another Alzheimer’s IPO

I’ve been saying a lot of unkind things about Axovant, the insta-company that’s taking a discarded GSK Alzheimer’s candidate and running with it. But thanks to Adam Feuerstein, I have another company to roll my eyes about. They have a completely different Alzheimer’s plan – they’ve taken a discarded Pfizer candidate and are running with it. The drug in question is azeliragon, formerly PF-04494700, targeting RAGE (the receptor for advanced glycation endpoints), and the company’s press material about it includes a qualifying statement that you don’t run across very often:

“Despite the 20mg/day dose being stopped by the DMC due to acute, reversible, concentration dependent cognitive worsening and the study being prematurely stopped for apparent futility, the study achieved its prespecified objective demonstrating a statistically significant 3.1 point different (p = 0.008) favoring azeliragon 5mg/day over placebo at 18 months in patients with mild to moderate AD.”

That’s in the ADASCog rating, but the overview goes on to say that “the study was not powered to show significant differences for global, functional, cognitive and behavioral secondary endpoints”. Here are some publications on the trials themselves. Now, being generous, one could conclude that there’s a chance for this to work – after all the 5mg/day numbers are, presumably, what they are. But at a 4x higher dose, big trial-ending trouble was seen, of just the sort that you can’t have in Alzheimer’s (“acute cognitive worsening”). And we have no idea where that kicks in between the two doses. This is a very, very tight window between what could be a good effect and what is certainly a very bad one, which is surely why Pfizer dropped the compound like it was giving off gamma rays and has not returned to it.

All Alzheimer’s clinical candidates are longshots, by definition. But this one is a longshot longshot. I hope that people are only putting money into it that they can afford to lose, but I also hope that when I see elderly customers shuffling up to the lottery ticket register, and I think I’m wrong about that one, too.

So who are these people? The company is vTv Therapeutics (that’s how they spell it), and they’re heading for an IPO. The bio of their CEO, Stephen Holcombe, says that he brings “brings over 23 years of financial and managerial experience” to the table. Looking closer, though, that experience is with KPMG Peat Marwick, a cell phone company, and an e-commerce provider to the construction industry. Unless he’s been hitting the books at night, and perhaps he has, one cannot guess that he knows anything about drug development. Their CSO is Carmen Valcarce, ex-Novo Nordisk. But the chairman of the board, that’s the really interesting part: it’s one Jeff Kindler, whom many will recognize as Pfizer’s onetime CEO. And there are many ex-Pfizer employees who have opinions on how much he knows about drug development, for sure. His departure from the company was the subject of a truly bizarre article the next year, one that I think set off a lot of discontent among the non-executive-suite folks at the company.

So vTv is going to be interesting to watch. The Alzheimer’s program isn’t their only shot, as opposed to Axovant, I will give them that. But some of their other assets have been kicking around for a while, too, such as the ones from when the company was known as TransTech Pharma (like TTP339, a glucokinase activator). Azeliragon itself was originally a TransTech compound, licensed to Pfizer, but it boomeranged back to them after the Phase II results. The company has changed its name and rebranded itself as an Alzheimer’s therapy play, and so off to the NASDAQ they go.

18 comments on “Another Alzheimer’s IPO”

Was 5mg/day the lowest dose in the trial? Could be more of a window on the low end, or via some multidose/day regimen (keep the concentration more level above some effective level and below the tox level.) Not a game I’d want to play with my money though.

“I hope that people are only putting money into it that they can afford to lose, but I also hope that when I see elderly customers shuffling up to the lottery ticket register, and I think I’m wrong about that one, too.”
Put the two together, and this business model starts to sound self-sustaining.
Okay, that was snarky and cruel even for me …

Sorry to be harping on this — but here is a project for any of you out there with access to a large clinical database. I’m a retired clinical neurologist with no academic affiliation, so there will be no competition from me.
Briefly, a drug in clinical use for over 40 years (Lopid aka Gemfibrozil) increases the amount of a ADAM10 (aka Kuzbanian), a protease which breaks down the Amyloid Precursor Protein (APP) in such fashion that it can’t form the Abeta peptide. So do people who’ve taken the drug have a decreased incidence of Alzheimer’s? The data is certainly out there waiting for you to mine.
The mechanism is somewhat byzantine, but the effect is real. I’ve tried to reach someone at Kaiser Permanente about it, but to no avail.
For more details please see — https://luysii.wordpress.com/2015/07/13/could-gemfibrozil-lopid-be-used-to-slow-down-or-even-treat-alzheimers-disease/

While it is true that Kinder was CEO at Pfizer for a spell, he is really a lawyer by training and trade.
He was clerk for Justice Brennan, a partner at Williams & Connolly, then worked in-house at GE and McDonald’s & Boston Market. Then he moved to GC of Pfizer.
Clearly a talented and successful big-law big-company guy. But this looks like VTVT is just buying his name and reputation.
The bigger red flag name @ VTVT is the guy nobody is talking about. Ron Perelman. He was also behind bio-stinker Nephros. Great piece on Nephros (NEPH) here:http://rgmcom.com/articles/nypost.html

But is the bigger joke that companies like this (and let’s not forget Flex Pharma, which raised nearly $90 million to develop Massaman curry to treat ” nocturnal leg cramps and spasms associated with severe neuromuscular conditions”) are able to raise astounding sums of money on such flimsy premises or that the rest of use aren’t? I’m not sure who the sucker is in this game.
A great strategy, though: sell a clinical candidate with a patina of legitimacy with trials that won’t read out for several years and sit back while the paper piles up: “That ain’t working, that’s the way you do it…..”

Going back to the article on Kindler, I had to laugh about the description of his time at McDonald’s:
“In 1996, at age 40, he became general counsel at McDonald’s …. Everyone at the fast-food company recognized Kindler’s abilities. He juggled complex intellectual issues with ease, made dazzling presentations, wielded a self-deprecating charm, and worked longer hours than anyone else.”
“complex intellectual issues”?? AT McDonald’s?
Kindler: “OK, first the patty, then the ketchup and then the mustard and pickle last!” If you put the pickle on first, there is a galvanic reaction between the burger, the pickle and the added layer of ketchup, with the ketchup acting as a proton acceptor”.
And why did he sign on to vTv with a compound that already has proved itself as virtually useless? Again from the article: “he was skeptical of what he was told, even when it came from people who knew far more about a subject than he did.”

Re #10 ” why did he sign on to vTv with a compound that already has proved itself as virtually useless? ”
From latest S-1/A:
“The services agreement for our Executive Chairman provides for a base fee of not less than $250,000. In addition to the IPO Equity Grants referred to above, our Executive Chairman shall be eligible to receive an annual performance bonus in respect of each completed fiscal year (commencing with fiscal year 2016) with a target value of $250,000 (payable in stock options, restricted stock or restricted stock units or, at our election, in cash). The actual payout may be higher or lower based on actual performance. The services agreement does not specify the performance metrics and goals for the annual target cash and equity awards, which metrics and goals will be established by the Compensation Committee at the beginning of each applicable fiscal year. ”
Quarter to a half mill/yr + free options for showing up to a few meetings a year. Nice work if you can get it…..

Frankly these companies are simply gambling on increases in stock value, rather than on rational expectations of having true disease-modifying drugs at hand. For example, the expected return on investment in terms of share price if the 1% chance of your drug beating p=0.05 in a clinical trial for Alzheimer’s disease is not so bad.
@luysii: Targeting a-secretases such as ADAM10, which cut in the middle of the amyloid peptide, is a common strategy in the search for drugs to treat Alzheimer’s disease. It is probably being investigated by several players large and small as we speak.
(@Derek: KPMG Peat Marwick is a management consultancy/financial services company with quite a respectable pedigree, in terms of such companies.)